The fungal pathogen Candida albicans causes diseases ranging from topical infections such as athlete’s foot and oral thrush to life-threatening systemic infections. Increasing incidence of infections and drug resistance support the need for new therapeutics.
Now, Galina Lepesheva, Ph.D., and colleagues report the catalytic properties, ligand-binding profiles and inhibition of activity of C. albicans CYP51 by clinical antifungal drugs and by an antifungal drug candidate, VT-1161.
The researchers found that the first-line treatment fluconazole was the weakest inhibitor of CYP51 and that posaconazole and VT-1161 were the strongest inhibitors. X-ray structures ofC. albicans CYP51 complexes with posaconazole and VT-1161 revealed molecular details that explain the potencies of these drugs.
The findings, reported in the Journal of Biological Chemistry, outline CYP51 features that could direct structure-based development of more efficient antifungal drugs.